Epidemiological data suggest that rates of cannabis use are increasing in women, who are particularly vulnerable to the negative consequences of cannabis use and at risk for an accelerated development of cannabis use disorders (CUD). Limited human and preclinical data suggest that women are more sensitive to the rewarding, reinforcing, behavioral, and cognitive effects of cannabis and its principal psychoactive component, delta-9-tetrahydrocannabinol (THC). However, this has not been adequately tested in humans. Gender differences are observed in the endocannabinoid system (related to estradiol in women) and in the metabolism of THC. Whether they are related to differences in the acute responses to THC between men and women has never been studied. In summary, the human data on the gender differences in the acute effects of cannabinoids remains scant. The overarching goal of this proposal is to address this lack of information by examining the gender related effects of THC in well-matched healthy women and men. We hypothesize that relative to men, women will have greater rewarding effects, lower verbal memory deficits and lower increases in serum cortisol induced by THC. Methods: Healthy male and female subjects (n=100) will receive THC or placebo in a double blind, randomized, crossover (2x2), and counterbalanced design. Subjective effects will be captured on a self-report visual analog scale of feeling states (VAS) before and at various time points after the drug infusions. Verbal learning and spatial working memory will be assessed using the Hopkins Verbal learning Task (HVLT) and the CANTAB battery respectively once per test day. Vital signs and blood for levels of THC, 11-OH-THC, THC- COOH, and cortisol will be collected before and at various time points after the infusion on each test day. Percent body fat, serum estradiol and menstrual cycle history (in women) will be collected at baseline on each test day. Safety assessments will be conducted during each test day, the day after, one month, and three months after study participation. It is hoped that data from this study will shed light on the gender differences in the acute effects of cannabinoids. These data will also provide the basis for future studies examining the underlying basis of the gender differences and in developing gender specific treatments for cannabis use disorders.